Non-melanoma skin cancers (NMSCs; cutaneous basal cell carcinomas and squamous cell carcinomas) are the most common malignancies in humans in the United States. They are the source of considerable morbidity and are a tremendous cost to the health care system. Current methods for their prevention have consisted primarily of sun and tanning bed avoidance and the regular use of sunscreens. Unfortunately, these measures have proven inadequate, and in contrast to most other malignancies, the incidence of NMSCs continues to increase. Two agents that show promise for the prevention of non-melanoma skin cancers are non-steroidal anti-inflammatory agents (NSAIDs), which inhibit the cyclooxygenase enzyme, and difluoromethylornithine (DFMO), a non-competitive inhibitor of the enzyme ornithine decarboxylase. In other organ systems, these agents have synergistic cancer chemopreventive activities. Because the skin is readily accessible, it may be possible to apply topical formulations of these agents for the chemoprevention of skin cancers without encountering the potential for systemic toxicity. We hypothesize that topical application of the COX inhibitor diclofenac and/or topical DFMO for 9 months is a safe and effective method of reversing biomarkers associated with the development of non-melanoma skin cancers in subjects at risk for their development and will prevent the onset of new actinic keratoses. To test our hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled trial of 100 subjects with a history of basal cell and/or squamous cell skin cancer and at least 8 actinic keratoses. Patients will be randomized to receive: topical DFMO + placebo; placebo + topical diclofenac; topical DFMO + topical diclofenac; placebo + placebo. We will assess whether topical DFMO + topical diclofenac alters skin biomarkers focusing on prostaglandin E2, polyamines and ornithine decarboxylase, proliferation and apoptosis markers (Ki67, PCNA, cyclin D1, caspase 3, tunel assay, Bcl-2, Bax), and molecules in the Akt/ERK1/2 axis. Studies are planned to determine if treatment with topical DFMO and/or topical diclofenac is well-tolerated without signs of significant toxicity. We will also assess whether subjects randomized to topical diclofenac and/or topical DFMO develop over a 9 month period of time fewer new actinic keratoses than those who are placed on placebo. The ultimate goal of these studies will be to determine whether topical diclofenac and/or DFMO should be evaluated in a clinical trial for the prevention of non-melanoma skin cancers.